Current thinking about the mechanism of carcinogenesis of human adenoviruses revolves around the capacity of different adenovirus serotypes to induce in infected or transformed cells the ability to succumb to or resist destruction by the specific (mediated by cytotoxic lymphocytes) or nonspecific (mediated by natural killer cells and macrophages) components of the cellular immune system. We have shown that the early genes of the nononcogenic human adenoviruses (Ad2, Ad5) induce in infected and transformed cells susceptibility to lysis by NK cells and macrophages while the early genes of highly oncogenic Ad12 induces either no susceptibility or induce resistance to NK cell lysis. Others have reported similar results and have also found that the Ad12 early genes interfere with the expression of class I major histocompatibility (MHC) antigens on the surface of Ad12 transformed rat and mouse cells thus removing a critical recognition signal for cytotoxic lymphocytes. We have now found the specific Ad2 and Ad5 early genes that induce susceptibility to NK cells and macrophages and have attempted to clarify the contribution toward tumorigenicity made by the expression of class I MHC antigens. This year we have identified the E1A oncogene of the nononcogenic Ad serotype as the gene that induces susceptibility to NK lysis and have found that both the E1A 12s and 13s transcription units can induce NK susceptibility. We have also found that Ad2 and Ad5 transformed mouse and hamster cells express levels of class I MHC antigens that are comparable to the levels present on Ad12 transformed cells. In spite of the loss of cell-surface class I antigens, the Ad2 and Ad5 transformed cells are unable to produce tumors in syngeneic adult hamsters and mice; Ad12 transformed cells from these species are highly tumorigenic in syngeneic adult animals. From these data it seems that there are barriers to tumorigenicity for cells transformed by Ad2 and Ad5 that are not relieved by reducing class I antigens and that Ad gene functions that govern the ability of transformed cells to be recognized and destroyed by NK cells and macrophages are among the primary determinants of the tumorigenicity of human Ad in rodents.